The Central Nervous System (CNS) has long been considered to be a site of relative immune privilege. However, it is increasingly recognized that CNS tissue injury in acute and chronic neurological disease may be mediated by the CNS inflammatory response. The CNS inflammatory response is primarily mediated by inflammatory cytokines.
Apolipoprotein E (ApoE) is a 299 amino acid lipid-carrying protein with a known sequence (Rall et al., J. Biol. Chem. 257:4174 (1982); McLean et al., J. Biol. Chem. 259:6498 (1984). The complete gene for human ApoE has also been sequenced (Paik et al., Proc. Natl. Acad. Sci. USA 82:3445 (1985). ApoE sequences from at least ten species have been determined, and show a high degree of conservations across species, except at the amino and carboxyl termini. Weisgraber, Advances in Protein Chemistry 45:249 (1994).
Human ApoE is found in three major isoforms: ApoE2, ApoE3, and ApoE4; these isoforms differ by amino acid substitutions at positions 112 and 158. The most common isoform is ApoE3, which contains cysteine at residue 112 and arginine at residue 158; ApoE2 is the least common isoform and contains cysteine at residues 112 and 158; ApoE4 contains arginine at residues 112 and 158. Additional rare sequence mutations of human ApoE are known (see, e.g, Weisgraber, Advances in Protein Chemistry 45:249 (1994),at page 268-269). The presence of ApoE4 has been associated with risk of developing sporadic and late-onset Alzheimer's disease (Strittmatter et al., Proc. Natl. Acad. Sci. USA 90:1977-1980 (1993)).
ApoE plays a role in cholesterol metabolism and has also been reported to have immunomodulatory properties. It is secreted by macrophages after peripheral nerve injury and by astrocytes and oligodendrocytes (glial cells) after Central Nervous System (CNS) injury.